Intrathecal delivery of frataxin mRNA encapsulated in lipid nanoparticles to dorsal root ganglia as a potential therapeutic for Friedreich's ataxia.

In Friedreich's ataxia (FRDA) patients, diminished frataxin (FXN) in sensory neurons is thought to yield the predominant pathology associated with disease. In this study, we demonstrate successful usage of RNA transcript therapy (RTT) as an exogenous human FXN supplementation strategy in vitro and in vivo, specifically to dorsal root ganglia (DRG). Initially, 293 T cells were transfected with codon optimized human FXN mRNA, which was translated to yield FXN protein.

Mutations in bone marrow-derived stromal stem cells unmask latent malignancy.

Neoplastic epithelia may remain dormant and clinically unapparent in human patients for decades. Multiple risk factors including mutations in tumor cells or the stromal cells may affect the switch from dormancy to malignancy. Gene mutations, including p53 mutations, within the stroma of tumors are associated with a worse clinical prognosis; however, it is not known if these stromal mutations can promote tumors in genetically at-risk tissue.

Unifying roles for regulatory T cells and inflammation in cancer.

Activities of CD4(+) regulatory (T(REG)) cells restore immune homeostasis during chronic inflammatory disorders. Roles for T(REG) cells in inflammation-associated cancers, however, are paradoxical. It is widely believed that T(REG) function in cancer mainly to suppress protective anticancer responses.

CD4+ lymphocytes modulate prostate cancer progression in mice.

Chronic inflammation contributes to the development of prostate cancer in humans. Here, we show that male Apc(Min/+) mice also develop prostate carcinoma with increasing age, mimicking that seen in humans in their 5th or 6th decade of life. Proinflammatory cytokines were significantly linked with cancer and increasing age in our mouse model; however, prostate and bowel tissues lacked evidence of inflammatory cell infiltrates other than mast cells.

Cytotoxic-T-lymphocyte-associated antigen 4 blockade abrogates protection by regulatory T cells in a mouse model of microbially induced innate immune-driven colitis.

Cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) expressed at high levels by CD4(+) CD25(+) CD45RB(low) regulatory T cells (Treg) is essential to their homeostatic and immunoregulatory functions. However, its relevance to anti-inflammatory roles of Treg in the context of colitogenic innate immune response during pathogenic bacterial infections has not been examined. We showed earlier in Rag2-deficient 129/SvEv mice that Treg cells are capable of suppressing colitis and colon cancer triggered by Helicobacter hepaticus, a widespread murine enterohepatic pathogen.

Mast cells are an essential hematopoietic component for polyp development.

It is generally agreed that most colon cancers develop from adenomatous polyps, and it is this fact on which screening strategies are based. Although there is overwhelming evidence to link intrinsic genetic lesions with the formation of these preneoplastic lesions, recent data suggest that the tumor stromal environment also plays an essential role in this disease. In particular, it has been suggested that CD34(+) immature myeloid precursor cells are required for tumor development and invasion.

T-cell function is critical for murine cholesterol gallstone formation.

Background & Aims: The formation of cholesterol gallstones is a complex process involving contributions from genes and environmental factors. Although gallbladder inflammation is believed to be common during cholelithogenesis, the role of immunologic factors is unknown.

Methods: The role of adaptive immunity in cholesterol cholelithogenesis was analyzed utilizing immunocompetent Helicobacter spp.

Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma.

Chronic inflammation of mucosal surfaces renders them increasingly susceptible to epithelial cancers both in humans and mice. We have previously shown that anti-inflammatory CD4(+)CD45RB(lo)CD25(+) regulatory (Treg or T(R)) lymphocytes down-regulate inflammation and block development of bacteria-triggered colitis and colorectal cancer (CRC) in 129/SvEv Rag2-/- mice. Interestingly, T(R) cells collected from Interleukin (IL)-10-deficient cell donors not only failed to suppress carcinogenesis but instead promoted invasive mucinous colonic carcinoma with a strong gender bias expressing in male mice.

Wild-type and interleukin-10-deficient regulatory T cells reduce effector T-cell-mediated gastroduodenitis in Rag2-/- mice, but only wild-type regulatory T cells suppress Helicobacter pylori gastritis.

CD4(+) CD45RB(hi) CD25(-) effector T cells (T(E)) promote Helicobacter pylori gastritis in mice, and CD4(+) CD45RB(lo) CD25(+) regulatory T cells (T(R)) are anti-inflammatory. Using adoptive transfer into H. pylori-infected Rag2(-/-) mice, we evaluated effects of wild-type (wt) C57BL/6 or congenic interleukin-10-deficient (IL-10(-/-)) T(R) cells on gastritis, gastric cytokines, and H.

Breast cancer: should gastrointestinal bacteria be on our radar screen?

Anti-inflammatory drugs and antibiotics alter the risk of breast cancer in women, but roles for bacteria and inflammation in breast malignancies are poorly understood. A recent study in mice suggests that intestinal bacteria can trigger mammary carcinoma. The mechanisms involved in this effect suggest that dysregulated host immune responses to enteric bacteria can influence the development of extraintestinal cancers, highlighting the opportunities for prevention and treatment aimed at promoting intestinal homeostasis.

Innate immune inflammatory response against enteric bacteria Helicobacter hepaticus induces mammary adenocarcinoma in mice.

Inflammation associated with bacterial infections is a risk factor for cancers in humans, yet its role in breast cancer remains poorly understood. We have previously shown that innate immune inflammatory response against intestinal bacteria is sufficient to induce colon cancer. Here we report that infecting Rag2-deficient C57BL/6 Apc(Min/+) mice with an intestinal bacterial pathogen, Helicobacter hepaticus, significantly promotes mammary carcinoma in females and enhances intestinal adenoma multiplicity by a tumor necrosis factor alpha (TNFalpha)-dependent mechanism.

Renal infarction and immune-mediated glomerulonephritis in sheep (Ovis aries) chronically implanted with indwelling catheters.

Microbial infections are common sequelae in humans and animals implanted with long-term intravascular catheters. Understanding the pathophysiology of infectious morbidity is critical to improving quality of care in catheterized subjects. Here, we describe findings in 6 clinically healthy, male sheep implanted with indwelling aortic or cardiac catheters for 6 to 10 mo.

Proinflammatory CD4+ CD45RB(hi) lymphocytes promote mammary and intestinal carcinogenesis in Apc(Min/+) mice.

Cancers of breast and bowel are increasingly frequent in humans. Chronic inflammation is known to be a risk factor for these malignancies, yet cellular and molecular mechanisms linking inflammation and carcinogenesis remain poorly understood. Here, we apply a widely used T-cell transfer paradigm, involving adoptive transfer of proinflammatory CD4+ CD45RB(hi) (T(E)) cells to induce inflammatory bowel disease (IBD) in mice, to investigate roles of inflammation on carcinogenesis in the Apc(Min/+) mouse model of intestinal polyposis.

CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice.

Colorectal cancer in humans results from sequential genetic changes in intestinal epithelia commencing with inactivation of the APC tumor suppressor gene. Roles for host immunity in epithelial tumorigenesis are poorly understood. It has been previously shown that CD4+CD25+ lymphocytes inhibit colitis-associated epithelial tumors in Rag-deficient mice.

CD4(+)CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice.

Roles for host immune response in carcinogenesis are not well defined. Recent studies have shown that microbially driven inflammation can lead to colon cancer and that prior transfer of regulatory lymphocytes expressing CD4 and CD25 prevents the innate inflammatory events that lead to colon cancer in mice. To further examine the ability of regulatory lymphocytes to inhibit carcinogenesis, 129/SvEv Rag-2-deficient mice were inoculated by gastric gavage with Helicobacter hepaticus, an enteric bacterial pathogen of mice.

Enhanced iodination of thyroglobulin facilitates processing and presentation of a cryptic pathogenic peptide.

Increased iodine intake has been associated with the development of experimental autoimmune thyroiditis (EAT), but the biological basis for this association remains poorly understood. One hypothesis has been that enhanced incorporation of iodine in thyroglobulin (Tg) promotes the generation of pathogenic T cell determinants. In this study we sought to test this by using the pathogenic nondominant A(s)-binding Tg peptides p2495 and p2694 as model Ags.